Document text
InterimClinical Study Report
Protocol C4591001
CLINICAL STUDY REPORT SYNOPSIS
CONFIDENTIAL
Page 1Vaccine Name and Compound Number: BNT162 RNA -Based COVID -19 Vaccines,
Compound Number: PF-07302048
Report Title: Final Analy sis Interim Report: A Phase 1/2/3, Placebo -Controlled,
Randomized, Observer -Blind, Dose -Finding Study to Evaluate the Safety , Tolerability ,
Immunogenicit y, and Efficacy of SARS -COV-2 RNA Vaccine Candidates Against COVID -
19 in Healthy Individuals
Protocol Number: C4591001
Sponsor: BioNTech
Sponsor Agent : Pfizer Inc
Phase of Development: Phase 1/2/3
First Subject First Visit: 29 April 2020
Last Subject Last Visit: Not applicable
Data Cutoff Date s:
24 August 2020 (Phase 1 safet y and immunogenicity data through 1 month after Dose 2)
02 September 2020 (Phase 2 safety data 7 day s after Dose 2 onl y)
04 November 2020 (Phase 2/3 first interim anal ysis for efficacy )
14 November 2020 (Phase 2/3 final anal ysis for efficacy , safety data 1 month after Dose 2
for 37,586 participants with a median of at least 2 months of follow-up, and available safet y
data for all 43,252 participants)
Serology Completion Date s:
17 September 2020 (Phase 1, Visit 7 [post -Dose 2 blood draw] assay completed)
12 October 2020 (Phase 2, Visit 3 [post -Dose 2 blood draw] assay completed)
Coordinating Investigator(s): Stephen Thomas, MD, SUNY Upstate Medical Universit y,
725Irving Ave, Ste. 311, Sy racuse, NY 13210
Refer to Appendix 16.1.4.1 for a list of investigators involved in this study .
Study Center(s): 131 in the United States, 9 in Turke y, 6 in Germany , 4 in South Africa,
2in Brazil, and 1 in Argentina . Refer to Appendix 16.1.4.1 for a list of sites involved in this
study.
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Page 2Date of Current Version: 03December 2020
Date(s) of Previous Report(s): Not applicable
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Page 3OBJECTIVES
Study Objectives and Endpoints:
Phase 1
Note: The primary safety estimand of serious adverse events (SAEs) from Dose 1 to
6months after the last dose is not presented in this interim clinical study report (CSR) but
will be summarized when results are av ailable.
Table S1.Phase 1 Objectives, Estimands, and Endpoints
Objectives Estimands Endpoints
Primary: Primary: Primary:
To describe the safety and
tolerability profiles of
prophylactic BNT162
vaccines in healthy adults
after 1 or 2 dosesIn participants receiving at least 1 dose of study
intervention, the percentage of participants reporting:
Local reactions for up to 7 days following each dose
Systemic events for up to 7 days following each dose
Adverse events (AEs) from Dose1 to 1 month after
the last dose
SAEs from Dose 1 to 6 months after the last doseLocal reactions (pain at the injection
site, redness, and swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, a nd
new or worsened joint pain)
AEs
SAEs
In addition, the percentage of participants with:
Abnormal hematology and chemistry laboratory
values 1and 7 days after Dose 1; and 7 days after
Dose 2
Grading shifts in hematology and chemistry
laboratory assessments between baseline and 1 and
7 days after Dose 1; and before Dose 2 and 7 days
after Dose 2Hematology and chemistry laboratory
parameters
Secondary: Secondary: Secondary:
To describe the immune
responses elicited by
prophylactic BNT162
vaccines in healthy adults
after 1 or 2 dosesIn participants complying with the key protocol criteria
(evaluable participants) at the following time points
after receipt of study intervention: 7 and 21 days after
Dose 1; 7 and 14 days and 1, 6, 12, and 24 months after
Dose 2
Geometric mean titers (GMTs) at each time point
Geometric mean fold rise (GMFR) from before
vaccination to each subsequent time point after
vaccination
Proportion of participants achieving ≥4-fold rise
from before vaccination to each subsequent time
point after vaccinationSevere acute respiratory syndrome
coronavirus 2 (SARS-CoV -2)
neutralizing titers
Geometric mean concentrations (GMCs) at each
time point
GMFR from prior to first dose of study intervention
to each subsequent time point
Proportion of participants achieving ≥4-fold rise
from before vaccination to each subsequent time
point after vaccinationS1-binding immunoglobulin G (IgG)
levels and receptor -binding domain
(RBD)-binding IgG levels
Geometric mean ratio (GMR), estimated by the ratio
of the geometric mean of SARS -CoV-2 neutralizing
titers to the geometric mean of binding IgG levels at
each time pointSARS-CoV-2 neutralizing titers
S1-binding IgG levels
RBD-binding IgG levels
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Page 4Phase 2/3
Note: The objectives, estimands, and endpoints presented in Table S2are from Protocol
Amendment 9. Theprimary safety estimand of SAEs from Dose 1 to 6 months after the
second dose in all participants in Phase 2/3, and mostimmunogenicity endpoints are not
presented in this interim CSR but will be summarized at a later time. Only the exploratory
immunogenicit y estimand of GMTs/GMCs and GMFRs at 1 month after Dose 2 for Phase 2
participants are presented.
Table S2. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints
Primary Efficacy
To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID -19 occurring from
7 days after the second dose in
participants with out evidence of
infection before vaccinationIn participants complying with the
key protocol criteria (evaluable
participants) at least 7 days after
receipt of the second dose of study
intervention: 100 × (1 –illness rate
ratio [IRR])
[ratio of active vaccine to placebo]COVID-19 incidence per
1000person-years of follow -up based on
central laboratory or locally confirmed
nucleic acid amplification test
(NAAT) in participants with no
serological or virological evidence (up to
7 days after receipt of the second dose) of
past SARS -CoV-2 infection
To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID -19 occurring from
7 days after the second dose in
participants with and without
evidence of infection before
vaccinationIn participants c omplying with the
key protocol criteria (evaluable
participants) at least 7 days after
receipt of the second dose of study
intervention: 100 × (1 –IRR)
[ratio of active vaccine to placebo]COVID-19 incidence per 1000 person -
years of follow -up based on c entral
laboratory or locally confirmed NAAT
Primary Safety
To define the safety profile of
prophylactic BNT162b2 in the first
360participants randomized (Phase 2)In participants receiving at least
1 dose of study intervention, the
percentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 7 days after
the second dose
SAEs from Dose 1 to 7 days after
the second doseLocal reactions (pain at the injection
site, redness, and swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, and new
or worsened joint pain)
AEs
SAEs
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Page 5Table S2. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints
To define the safety profile of
prophylactic BNT162b2 in all
participants randomized in Phase 2/3In participants receiving at least
1 dose of study intervention, the
percentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month after
the second dose
SAEs from Dose 1 to 6 months
after the second doseAEs
SAEs
In a subset of at least 6000 participants:
oLocal reactions (pain at the
injection site, redness, and
swelling)
oSystemic events (fever, fatigue,
headache, chills, vomiting,
diarrhea, new or worsened
muscle pain, and new or
worsened joint pain)
To define the safety profile of
prophylactic BNT162b2 in
participants 12 to 15 years of age in
Phase 3In participants receiving at least
1dose of study inter vention, the
percentage of participants reporting:
Local reactions for up to 7 days
following each dose
Systemic events for up to 7 days
following each dose
AEs from Dose 1 to 1 month
after the second dose
SAEs from Dose 1 to 6 months
after the second doseLocal reactions (pain at the injection
site, redness, and swelling)
Systemic events (fever, fatigue,
headache, chills, vomiting, diarrhea,
new or worsened muscle pain, and
new or worsened joint pain)
AEs
SAEs
Secondary Efficacy
To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID -19 occurring from
14 days after the second dose in
participants without evidence of
infection before vaccinationIn participants complying with the
key protocol criteria (evaluable
participants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 –IRR) [ratio of active
vaccine to placebo]COVID-19 incidence per 1000
person-years of follow -up based on
central laboratory or locally confirmed
NAAT in participants with no serologica l
or virological evidence (up to 14 days
after receipt of the second dose) of past
SARS-CoV-2 infection
To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed COVID -19 occurring from
14 days after the second dose in
participants with and without
evidence of infection before
vaccinationIn participants complying with the
key protocol criteria (evaluable
participants) at least 14 days after
receipt of the second dose of study
intervention:
100 × (1 –IRR) [ratio of active
vaccine to placebo]COVID-19 incidence per 1000
person-years of follow -up based on
central laboratory or locally confirmed
NAAT
To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed severe COVID -19
occurring from 7 days and from
14days after the second dose in
participants without evidence of
infection before vaccinationIn participants complying with the
key protocol criteria (evaluable
participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of
study intervention: 100 × (1 –IRR)
[ratio of active vaccine to placebo]Confirmed severe COVID -19 incidence
per 1000 person -years of follow -up in
participants with no serological or
virological evidence (up to 7 days and up
to 14 days after receipt of the second
dose) of past SARS -CoV-2 infection
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Page 6Table S2. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints
To evaluate the efficacy of
prophylactic BNT162b2 against
confirmed severe COVID -19
occurring from 7 days and from
14days after the second dose in
participants with and with out
evidence of infection before
vaccinationIn participants complying with the
key protocol criteria (evaluable
participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of
study intervention: 100 × (1 –IRR)
[ratio of active vaccine to placebo]Confirmed severe COVID -19 incidence
per 1000 person -years of follow -up
To describe the efficacy of
prophylactic BNT162b2 against
confirmed COVID -19 (according to
the Centers for Disease Control and
Prevention (United States)
(CDC)-defined symptoms) occurring
from 7 days and from 14 days after
the second dose in participants
without evidence of infection before
vaccinationIn participants complying with the
key protocol criteria (evaluable
participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of
study intervention: 100 × (1 –IRR)
[ratio of active vaccine to placebo]COVID-19 incidence per 1000 person -
years of follow -up based on central
laboratory or locally confirmed NAAT in
participants with no serolog ical or
virological evidence (up to 7 days and up
to 14days after receipt of the second
dose) of past SARS-CoV -2 infection
To describe the efficacy of
prophylactic BNT162b2 against
confirmed COVID -19 (according to
the CDC-defined symptoms)
occurring from 7 days and from
14days after the second dose in
participants with and without
evidence of infection before
vaccinationIn participants complying with the
key protocol criteria (evaluable
participants)
at least 7 days
and
at least 14 days
after receipt of the second dose of
study intervention: 100 × (1 –IRR)
[ratio of active vaccine to placebo]COVID-19 incidence per 1000 person -
years of follow -up based on central
laboratory or locally confirmed NAAT
Secondary Immunogenicity
To demonstrate the noninferiority of
the immune response to prophylactic
BNT162b2 in participants 12 to 15
years of age compared to participants
16 to 25 years of ageGMR, estimated by the ratio of the
geometric mean of SARS -CoV-2
neutralizing titers in the 2 age groups
(12-15 years of age to 16 -25 years of
age) 1 month after completion of
vaccinationSARS-CoV-2 neutralizing titers in
participants with no serological or
virological evidence (up to 1 month after
receipt of the second dose) of past SARS-
CoV-2 infection
Exploratory
To evaluate the immune response
over time to prophylactic BNT162b2
and persistence of immune response
in participants with and without
serological or virological evidence of
SARS-CoV-2 infection before
vaccinationGMC/GMT, GMFR, and p ercentage
of participants with titers greater than
defined threshold(s), at baseline and
1, 6, 12, and 24 months after
completion of vaccinationS1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers
To evaluate the immune response
(non-S) to SARS -CoV-2 in
participants with and without
confirmed COVID -19 during the
studySARS-CoV-2 nucleoprotein
binding(N-binding ) antibody
To describe the serological responses
to the BNT vaccine candidate in cases
of:
Confirmed COVID-19
Confirmed severe COVID -19S1-binding IgG levels and/or
RBD-binding IgG levels
SARS-CoV-2 neutralizing titers
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Page 7Table S2. Phase 2/3 Objectives, Estimands, and Endpoints
Objectivesa Estimands Endpoints
SARS-CoV-2 infection without
confirmed COVID -19
To describe the safety,
immunogenicity, and efficacy of
prophylactic BNT162b2 in
individuals with confirmed stable
HIV diseaseAll safety, immunogenicity, and
efficacy endpoints described above
To describe the safety and
immunogenicity of prophylactic
BNT162b2 in individuals 16 to 55
years of age vaccinated with study
intervention produced by
manufacturing “Process 1” or
“Process 2”All safety endpoints described above
SARS-CoV-2 neutralizing titers
a.HIV-positive participants in Phase 3 were not included in analyses of the objectives, with the exception of the specific
exploratory objective.
METHODS
Study Design: This is a Phase 1/2/3, randomized, multinational, placebo -controlled,
observer-blind, dose -finding, vaccine candidate– selection, and efficacy study in healthy
individuals.
The study consists of 2 parts: Phase 1 to identify preferred vaccine candidate(s) and dose
level(s); and Phase 2/3 as an expanded cohort and efficacy part. These parts, and the
progression between them, are detailed in Figure S1.
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Page 8Figure S1.Study Schema
Phase 1 For each vaccine candidate (4:1 randomization active:placebo)
Age: 18-55 y Age: 65-85 y
Low-dose-level 2-dose group (n=15)
IRC (safety) IRC (safetyLow-dose-level 2-dose group (n=15)after Dose 1)
Mid-dose-level 2-dose group (n=15)
IRC (safety)IRC (safetyMid-dose-level 2-dose group (n=15)after Dose 1)
High-dose-level 2-dose group (n=15)
IRC (safetyHigh-dose-level 2-dose group (n=15)after Dose 1)
IRC choice of group(s) for Phase 2/3
(safety & immunogenicity after Doses 1 and 2)
Phase 2/3 Single vaccine candidate (1:1 randomization active:placebo)
Safety and immunogenicity analysis of
Phase 2 data (first 360 participants)
by unblinded team (these participants
will also be included in Phase 3
analyses)Age: ≥12
(Stratified 12 -15, 16-55, or >55)
BNT162b2 30 µg or placebo 2 doses
(n~21,999 per group, total n~43,998)
Abbreviation: IRC = internal review committee
The study evaluated the safet y, tolerability , and immunogenicit y of 2 different SARS -CoV-2
RNA vaccine candidates against COVID- 19 and the Phase2/3 efficacy of 1 selected
candidate based on Phase 1 results:
As a 2-dose (separated by 21 days) schedule;
At various dose levels in Phase 1;
In various age groups:
Phase 1: 18 to 55 y ears of age, 65 to 85 y ears of age;
Phase 2: ≥18 years of age (stratified as 18 to 55 years and >55 to 85 years);
Phase 3: ≥12 years of age (stratified as 12 to 15, 16 to 55, or >55 y ears of age).
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Page 9To facilitate rapid review of data in real time, Pfizer and BioNTech staff were unblinded to
vaccine allocation for the participants in Phase 1 and remainblinded for the Phase 2/3
portion of study except those who were designated for unblinded activities following the
protocol and the data blinding plan .
Phase 1
Each group (vaccine candidate/dose level/age group) was comprised of 15 participants
randomized 4:1 to receive active vaccine or placebo (12participants randomized to active
vaccine and 3 to placebo, such that the placebo participants across the groups would produce
a roughly comparabl y-sized cohort).
For each vaccine candidate/dose level/age group, safety precautions included: additional
safety assessments, controlled enrollment, application of stopping rules, and I RC review of
safety data to determine if dose escalation could proceed.
Groups of participants 65 to 85 y ears of age were not started until safet y data for the RNA
platform wer e deemed acceptable at the same, or a higher, dose level in the 18 to 55 years of
age group b y the IRC.
In this phase, 13 groups were studied, corresponding to a total of 195 participants.
Following review of all available safety and immunogenicity data through 14 day s after
Dose2 for BNT162b1 and BNT162b2, both vaccine constructs were considered strong
candidates to proceed to Phase 2/3.
Phase 2/3
Safety and immunogenicity data generated during the Phase 1 portion of this study and the
BioNTech study conducted in German y (BNT162 -01) supported BNT162b2 at a dose of
30µg as the vaccine candidate to proceed into Phase 2/3.
The Phase 2 part of the study was comprised of the first 360 participants enrolled (1:1
randomization between BNT162b2 and placebo, st ratified by age groups [18 to 55 years and
>55 to 85 y ears] with approximately 50% in each age stratum) to assess s afety data through
7days after Dose 2 and immunogenicit y data. Enrollment continued during Phase 2 and
these participants are included in t he efficacy evaluation in the Phase 3 part of the study .
Participants in the ongoing Phase 3 part of the study are ≥12years of age (stratified as 12 to
15, 16 to 55, or >55 years of age). The 12 -to 15-year stratum will comprise up to
approximately 2000participants enrolled at selected investigational sites. It was planned to
enrolla minimum of 40% of participants in the >55 years of age stratum. Participants in
Phase3 were randomized 1:1 to receive active vaccine or placebo.
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Page 10The Phase 2/3 part of the study is event-driven. Under the assumption of a true vaccine
efficacy (VE) rate of ≥60%, a target of 164 primary -endpoint cases of confirmed COVID -19
occurring at least 7 days following the second dose of the primary series of the candidate
vaccine will be sufficient to provide 90% power to conclude true VE >30% with high
probability . The total number of participants enrolled in Phase 2/3 may vary depending on
the incidence of COVID -19 at the time of the enrollment, the true underl ying VE, and a
potential earl y stop for efficacy or futility.
Assuming a COVID -19 attack rate of 1.3% per y ear in the placebo group, accrual of 164 first
primary-endpoint cases within 6 months, an estimated 20%non -evaluable rate, and
1:1randomization, the BNT162b2 vaccine candidate selected for Phase 2/3 is expected to
comprise approximately 21,999 vaccine recipients per group, for a total sample size of
43,998. This is the number of participants initially targeted for Phase 2/3 and may be
adjusted based on advice from DM C analyses of case accumulation and the percentage of
participants who are seropositive at baseline. Dependent upon the evolution of the pandemic,
it is possible that the COVID -19 attack rate may be higher, in which case accrual would be
expected to be mo re rapid, enabling the study ’s primary endpoint to be evaluated sooner.
In Phase 3, noninferiority of immune response to prophylactic BNT162b2 in participants
12to 15 years of age to response in participants 16 to 25 y ears of age will be assessed based
on the GMR of SARS -CoV-2 neutralizing titers using a 1.5 -fold margin.
The safety and immunogenicity of prophy lactic BNT162b2 in individuals 16 to 55 y ears of
age vaccinated with BNT162b2 manufactured with “Process 1” and each lot of BNT162b2
manufactured with “Process 2” , which was developed to support an increased scale of
manufacture, will be described.
It is planned that participants would participate for approximately 26months.
Inclusion/Exclusion Criteria: Participants were eligible to be included in the study only if
all of the following criteria apply :
Inclusion Criteria:
Age and Sex:
1.Male or female participants between the ages of 18 and 55 y ears, inclu sive, 65 and
85years, inclusive (Phase 1), or ≥12 years (Phase 2/3), at randomization. Note that
participants <18 years of age cannot be enrolled in the EU.
Type of Participant and Disease Characteristics:
2.Participants who were willing and able to comply with all scheduled visits, vaccination
plan, laboratory tests, lifesty le considerations, and other study procedures.
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Page 113.Healthy participants who were determined b y medical history, ph ysical examination
(ifrequired), and clinical judgment of the investigator to be eligible for inclusion in the
study.
Note: Healthy participants with preexisting stable disease, defined as disease not requiring
significant change in therapy or hospitalization for worsening disease during the 6 weeks
before enrollment, could be in cluded.
4.Phase 2/3 only: Participants who, in the judgment of the investigator, were at higher risk
for acquiring COVID -19 (including, but not limited to, use of mass transportation,
relevant demographics, and frontline essential workers).
Informed Consent:
5. Capable of giving personal signed informed consent/have parent(s)/legal guardian
capable of giving signed informed consent which included compliance with the
requirements and restrictions listed in the informed consent document (ICD) and in the
protocol.
Exclusion Criteria:
Participants were excluded from the stud y if any of the following criteria applied:
Medical Conditions:
1.Other medical or psy chiatric condition including recent (within the past year) or active
suicidal ideation/behavior or laboratory abnormality that increased the risk of study
participation or, in the investigator’s judgment, made the participant inappropriate for the
study.
2.Phases 1 and 2 only: Known infection with human immunodeficiency virus (HIV),
hepatitis C virus (HCV), or hepat itis B virus (HBV).
3.History of severe adverse reaction associated with a vaccine and/or severe allergic
reaction (eg, anaph ylaxis) to any component of the study intervention(s).
4.Receipt of medications intended to prevent COVID -19.
5.Previousclinical (based on COVID -19 symptoms/signs alone, if a SARS -CoV-2 NAAT
result was not available) or microbiological (based on COVID -19 symptoms/signs and a
positive SARS -CoV-2 NAAT result) diagnosis of COVID -19.
6.Phase 1 only: Individuals at high risk for severe COVID -19, including those with any of
the following risk factors:
Hypertension
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Page 12Diabetes mellitus
Chronic pulmonary disease
Asthma
Current vaping or smoking
History of chronic smoking within the prior y ear
Chronic liver disease
Stage 3 or worse chronic kidney disease(glomerular filtration rate <60 mL/min/1.73 m2)
Resident in a long- term facility
Body mass index (BMI) >30 kg/m2
Anticipating the need for immunosuppressive treatment within the next 6 months
7.Phase 1 only: Individuals currentl y working in occupations with high risk of exposure to
SARS-CoV-2 (eg, healthcare worker, emergency response personnel).
8. Immunocompromised individuals with known or suspected immunodeficiency , as
determined b y history and/or laboratory /physical examination.
9.Phase 1 only: Individuals w ith a history of autoimmune disease or an active autoimmune
disease requiring therapeutic intervention, including but not limited to: sy stemic or
cutaneous lupus ery thematosus, autoimmune arthritis/rheumatoid arthritis, Guillain -Barré
syndrome, multiple sc lerosis, Sjögren’s s yndrome, idiopathic thrombocytopenia purpura,
glomerulonephritis, autoimmune thy roiditis, giant cell arteritis (temporal arteritis),
psoriasis, and insulin -dependent diabetes mellitus (type 1).
10. Bleeding diathesis or condition associated with prolonged bleeding that would, in the
opinion of the investigator, contraindicate intramuscular injection.
11.Women who are pregnant or breastfeeding.
Prior/Concomitant Therapy:
12.Previous vaccination with any coronavirus vaccine.
13.Individuals who received treatment with immunosuppressive therap y, including cytotoxic
agents or s ystemic corticosteroids, eg, for cancer or an autoimmune disease, or planned
receipt throughout the study . If systemic corticosteroids were administered short term
(<14days) for treatment of an acute illness, participants should not have been enrolled
into the study until corticosteroid therapy had been discontinued for at least 28 day s
before stud y intervention administration. I nhaled/nebulized (except for participants in
Phase 1 – see exclusion criterion 14), intra- articular, intrabursal, or topical (skin or ey es)
corticosteroids were permitted.
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Page 1314.Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
15.Receipt of blood/plasma products or immunoglobulin, from 60 day s before study
intervention administration or planned receipt throughout the stud y.
Prior/Concurrent Clinical Study Experience:
16.Participation in other studies involving study intervention within 28 day s prior to study
entry and/or during study participation.
17.Previous participation in other studies involving study intervention containing lipid
nanoparticles.
Diagnostic Assessments:
18.Phase 1 only: Positive serological test for SARS- CoV-2 immunoglobulin M (IgM)
and/or IgG antibodies at the screening visit.
19.Phase 1 on ly:Any screening hematology and/or blood chemistry laboratory value that
meets the definition of a ≥Grade 1 abnormality .
Note:With the exception of bilirubin, participants with any stable Grade 1 abnormalities
(according to the toxicity grading scale) m ay be considered eligible at the discretion of
the investigator. (Note: A “stable” Grade 1 laboratory abnormalit y is defined as a report
of Grade 1 on an initial blood sample that remains ≤ Grade 1 upon repeat testing on a
second sample from the same participant.)
20.Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B
core antibodies (HBc Abs), or hepatitis C virus antibodies (HCVAbs) at the screening
visit.
21.Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hou rs before receipt of
study intervention.
Other Exclusions:
22.Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of
the study, site staff otherwise supervised by the investigator, and their respective famil y
members.
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Page 14Vaccines Administered: The study evaluated a 2 -dose (separated b y 21 days) schedule of
2investigational RNA vaccine candidates for active immunization against COVID -19 or
saline placebo:
BNT162b1 (BNT162 RNA -lipid nanoparticle (LNP) vaccine containing
nucleoside -modified messenger ribonucleic acid (modRNA) that encodes the RBD):
10µg, 20 µg, 30 µg, 100 µg
BNT162b2 (BNT162 RNA -LNP vaccine containing modRNA that encodes SARS- CoV-
2 full-length, P2 mutant, prefusion spike gl ycoprotein (P2 S): 10 µg, 20µg, 30µg
Normal saline (0.9% sodium chloride solution for injection)
The vaccine candidate selected for Phase 2/3 evaluation was BNT162b2 at a dose of 30 µg.
A list of the study interventions administered in this study and their representative lot
numbers is provided inTable S3.
Table S3. Investigational Product Lot Numbers – Final Analysis Interim
Investigational
Product PhaseManufacturerVendor Lot Number
(Manufacturer)
Lot Numbera(Pfizer)
BNT162b1 (10 µg,
20µg, 30 µg, and
100µg)1BioNTech BCV10320 -A E220395-0001L
BNT162b2 (10 µg,
20µg, and 30 µg)1BioNTech BCV40420 -A E220395-0004L
Normal saline (0.9%
sodium chloride
solution for injection)1Pfizer DK1589 20-001592
BNT162b2 (30 µg) 2/3BioNTech BCV40420 -A
BCV40420 -A
BCV40420 -A
BCV40420 -A
BCV40420 -A
BCV40620 -A
BCV40620 -AE220395-
0006L003/P220395 -
0012L
E220395-
0035L002/P220395 -
0048L
E220395-
0035L003/P220395 -
0048L
EU2065896/E220395 -
0004L
PA2070104/P220395 -
0008L
PA2071394/P220395 -
0029L
PA2072393/P220395 -
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Page 15Table S3. Investigational Product Lot Numbers – Final Analysis Interim
BCV40620 -B
BCV40620 -B
BCV40620 -C
BCV40620 -C
BCV40620 -D
BCV40620 -D
BCV40720 -A
BCV40720 -A
BCV40720 -B
BCV40720 -C
ED39380019L
PA2071395/P220395 -
0016L
PA2072396/P220395 -
0016L
PA2071396/P220395 -
0047L
PA2072439/P220395 -
0047L
PA2072442/P220395 -
0042L
PA2072765/P220395 -
0042L
PA2074172/P220395 -
0053L
PA2074998/P220395 -
0060L
PA2074173/P220395 -
0051L
PA2074071/P220395 -
0052L
PA2074300/P220395 -
0021L
ED3938
ED3938
ED3938
EE3813
EE3813
EE8493ZEU2074330/E220395 -
0036L
PA2074300/P220395 -
0022L
PA2074300/P220395 -
0023L
PA2074838/P220395 -
0024L
PA2074838/P220395 -
0020L
PA2077905/P220395 -
0026L
Normal saline (0.9%
sodium chloride
solution for injection)2/3Pfizer DK1589;20 -001592
DK1589;20 -001776
DK2074;20 -002029
DK2074;20 -002108
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221PA2064251/P220395 -
0005L
PA2065311/P220395 -
0007L
PA2067775/P220395 -
0030L
PA2067774/P220395 -
0013L
PA2069407/P220395 -
0031L
PA2069407/P220395 -
0032L
PA2069407/P220395 -
0033L
PA2069407/P220395 -
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Page 16Table S3. Investigational Product Lot Numbers – Final Analysis Interim
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -002221
DK2074;20 -0022210034L
PA2069407/P220395 -
0044L
PA2069407/P220395 -
0045L
PA2069407/P220395 -
0046L
PA2069407/P220395 -
0054L
PA2069407/P220395 -
0055L
PA2069407/P220395 -
0056L
PA2069407/P220395 -
0062L
PA2069407/P22039 5-
0065L
PA2069407OTH/E220395 -
0049L
Note: C4591001 End of Study Information and Quality Control (QC) Record for Study Drug Appendix (Section D)
dated 19Nov2020 w as used to create this table.
a. Lot number assigned to the investigational product by Pfizer Global Clinical Supply.
Protocol C4591001 Investigational Product Lot Numbers Table – Final Analysis Interim, Final, Version 1.0,
19Nov2020.
Efficacy and Immunogenicity Evaluations: Efficacy was assessed for potential cases of
COVID-19.
Confirmed severe COVID- 19: confirmed COVID -19 and presence of at least 1 of the
following:
Clinical signs at rest indicative of severe s ystemic illness (RR ≥30 breaths per minute,
HR ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2
<300mm Hg);
Respiratory failure (defined as needing high -flow oxygen, noninvasive ventilation,
mechanical ventilation, or ECMO);
Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors);
Significant acute renal, hepatic, or neurologic d ysfunction*;
Admission to an I CU;
Death.
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Page 17For immunogenicity testing, the following assay s were performed inPhase 1 and Phase 2 and
will be performed in Phase 2 /3, with the exception of the RBD -binding IgG assay :
SARS-CoV-2 neutralizing titers
Antigen binding antibodies specific to SARS -CoV-2
RBD-binding IgG levels (most relevant to BNT162b1, which encodes the RBD)
S1-binding IgG levels (most relevant to BNT162b2 which encodes P2 S)
N-binding antibody (Phase 2/3 only )
Safety Evaluations:
Clinical Safety Laboratory Assessments (Phase 1 only ):All protocol -required laboratory
assessments, were conducted in accordance with the laboratory manual and the Schedule of
Activities. Unscheduled clinical laboratory measurements were obtained at any time during
the study to assess any perceived safety issues.
The investigator reviewed the laboratory report, documented this review, and recorded any
clinically relevant changes occurring during the study in the AE section of the case report
form (CRF). All laboratory tests with values considered clinicall y significantly abnormal
during participation in the study or within 28 day s after the last dose of study intervention
were repeated until the values returned to normal or baseline or were no longer considered
clinically significant b y the investigator or medical monitor. I f such values did not return to
normal/baseline within a period of time judged reasonable by the investigator, the etiology
was identified, and Pfizer and BioNTech notified.
Local Reactions and Systemic Events: All participants in Phase 1 and a subset of at least the
first 6000 participants randomized in Phase 2/3 were asked to monitor and record local
reactions, s ystemic events, and antipy retic/pain medication usage for 7 days following
administration of the study intervention using an e -diary. Anyparticipants in Phase 3 who
are HIV-positive or 12 to 15 y ears of age may also have been included in this subset (will be
reported at a later time ). In addition, participants 16 through 17 years of age enrolled under
Protocol Amendment 9 (finalized 29 October2020) and onwards will be included in the
reactogenicity subset. For participants who are not in the reactogenicity subset, local
reactions and s ystemic events consistent with reactogenicity weredetected and reported as
AEs.
For local reactogenicit y, during the reactogenicit y e-diary reporting period, participants were
asked to assess redness, swelling, and pain at the injection site and to record the sy mptoms in
the reactogenicit y e-diary. Ifa local reaction persisted bey ond the end of the reactogenicit y
e-diary period following vaccination, the participant was requested to report that information.
Redness and swelling were measured and recorded in measuring device units (range: 1to21)
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Page 18andthen categorized during anal ysis as absent, mild, moderate, or severe based on the
grading scale. Pain at the injection site was assessed by the participant as absent, mild,
moderate, or severe according the grading scale.
For systemic reactogenicity , during the reactogenicity e-diary reporting period, participants
were asked to assess vomiting, diarrhea, headache, fatigue, chills, new or worsened muscle
pain, and new or worsened joint pain and to record the sy mptoms in the reactogenicit y e-
diary. The symptoms were assessed by the participant as absent, mild, moderate, or severe
according to the grading scale.
Temperature was collected in the reactogenicit y e-diary in the evening daily during the
reactogenicity e-diary reporting period and at an y time during the reactogenicity e-diary data
collection periods when fever was suspected. Fever is defined as an oral temperature of
≥38.0°C (100.4°F). The highest temperature for each day was recorded in the reactogenicit y
e-diary.
The investigator or designee obtained stop dates from the participant for any ongoing local
reactions, s ystemic events, or use of antipy retic medication on the last day that the
reactogenicity e-diary was completed.
AEs and SAEs : AEs were reported b y theparticipant (or, when appropriate, by a caregiver,
surrogate, or the participant's legally authorized representative). The time period for activel y
eliciting and collecting AEs and SAEs (“active collection period”) for each participant began
from the tim e the participant provided informed consent, which was obtained before the
participant’s participation in the study (ie, before undergoing any study-related procedure
and/or receiving study intervention), through and including Visit 7(1 month after Dose 2 )for
Phase 1 participants, and Visit 3 (1 month after Dose 2) for Phase 2/3 participants. I n
addition, any AEs occurring up to 48 hours after each subsequent blood draw were recorded
on the CRF. SAEs were collected from the time the participant provides informed consent to
approximately 6 months after the last dose of study intervention (Visit 8 for Phase 1
participants and Visit 4 for Phase 2/3 participants).
Acute reactions (immediate AEs) were collected within the first 4 hours after administration
of the study intervention (for the first 5 participants vaccinated in each Phase 1 group), and
within the first 30 minutes (for the remainder of participants).
Statistical Methods:
Efficacy Analysis: The efficacy assessment in Phase 2/3 portion of the study was event -
driven. Initially, 4interim analy ses were planned to be performed by an unblinded statistical
team supporting the DMC after accrual of at least 32, 62, 92, and 120 confirmed COVID -19
cases, with the final analy sis performed after accrual of at least 164 cases. For operational
reasons, the first planned IA (after at least 32 cases) was not performed. Protocol
Amendment 9 eliminated the planned interim analysis with atleast32 cases and pr ovided for
3interim analy ses to be performed after accrual of at least 62, 92, and 120 cases. At each of
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Page 19the IAs, vaccine efficacy with respect to the first primary efficacy endpoint was to be
assessed. At the final analy sis (atleast 164 cases) vaccine efficacy with respect to all
efficacy endpoints was to be assessed.
Assessment of VE of BNT162b2 for the first primary efficacy endpoint was performed for
confirmed COVID -19 cases observed at least 7 day s after the receipt of Dose 2 onwards
among particip ants without serological or virological evidence (up to 7 days after receipt of
the second dose) of past SARS -CoV-2 infection. VE was estimated b y 100% × (1 –IRR),
where IRR was the ratio of COVID -19 illness rate in the BNT162b2 group to the
correspondin g illness rate in the placebo group. The Bay esian 95% credible interval and the
posterior probability for the true vaccine efficacy greater than 30% conditioning on the
available data, i.e. P[VE >30%|data], were calculated using a beta -binomial model and a
pre-specified minimally informative beta distribution as prior. The calculation of posterior
probability and 95% credible interval were adjusted for surveillance time. All efficacy
endpoints were to be analy zed using the same Bayesian approach unless st ated otherwise.
If the posterior probability of VE>30% is greater than 99.5% at an y pre-planned interim
analysis, or greater than 98.6% at the final anal ysis, the vaccine efficacy of BNT162b2 would
be declared.
If the predicted posterior probability of demonstrating vaccine efficacy at the final anal ysis is
less than 5.0% at an y of the first 2 planned interim anal yses, the stud y would stop for lack of
benefit (futility ).
For the subgroup analyses of the efficacy endpoints, and for the anal yses of efficacy for
COVID-19 cases determined according to the CDC -defined symptoms, VE and the 2 -sided
95% confidence interval (CI)for VE was derived based on the Clopper and Pearson method
adjusted for surveillance time .
Immunogenicity Analysis: For immunogenicity results of SARS -CoV-2 neutralizing titers
and S1-or RBD-binding IgG concentrations, the GMT or GMCs were computed along with
associated 95% confidence intervals (CIs). The GMT and GMC were calculated as the
meansof assay results after making the logarithm transformation and then exponentiating the
means to express results on the original scale. Two- sided 95% CIs were obtained by taking
log transforms of assay results, calculating the 95% CIswith reference to Student’s t -
distribution, and then exponentiat ing the confidence limits.
The GMFR was calculated by exponentiating the mean of the difference of logarithmicall y
transformed assay results (later time point – earlier time point). Two -sided CIs were
obtained by calculating CI s using Student’s t -distribution for the mean difference of the
logarithmicall y transformed assay results and exponentiating the confidence limits.
The GMR was calculated as the mean of the difference of logarithmically transformed assay
results (eg, SARS-CoV-2 neutralizing titers minus S1 -binding IgG levels for each
participant) and exponentiating the mean. Two -sided CIs were obtained by calculating CIs
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Page 20using Student’s t -distribution for the mean difference of the logarithmically transformed
assay results and exponentiating the co nfidence limits.
The exact 95% CIs for binary endpoints were computed using the F distribution
(Clopper-Pearson method).
Titers/concentrations below the lower limit of quantitation (LLOQ) or denoted as below the
level of quantitation (BLQ) were set to 0.5 × LLOQ for analy sis.
For participants with no serological or virological evidence (up to 1 month after receipt of the
second dose) of past SARS -CoV-2 infection, the GMR of SARS -CoV-2 neutralizing titers in
participants 12 to 15 y ears of age to those in par ticipants 16 to 25 y ears of age and 2 -sided
95% CIs will be provided at 1 month after Dose 2 for noninferiority assessment. The GMR
and its 2-sided 95% CI will be derived by calculating differences in means and CI s on the
natural log scale of the titers b ased on the Student’s t -distribution and then exponentiating the
results. The difference in means on the natural log scale will be 12 to 15 years minus 16 to
25 years. Noninferiorit y will be declared if the lower bound of the 2 -sided 95% CI for the
GMR is greater than 0.67.
Safety Analysis: The primary safet y objective was evaluated b y descriptive summary
statistics for local reactions, sy stemic events, AEs/SAEs, and abnormal hematology and
chemistry laboratory parameters (Phase 1 only ), for each vaccine group. A 3- tier approach
was used to summarize AEs in Phase 2/3. Under this approach ,AEs were classified into 1 of
3tiers:
Tier 1 events are prespecified events of clinical importance and are identified in a list in
the product’s Safety Review Plan; there are no Tier 1 AEs identified for this program.
Tier 2 events were those that were not Tier 1 but were considered “relatively common”;
aMedDRA preferred term is defined as a Tier 2 event if there are at least 1% of
participants with the AE term in at least 1 vaccine group .
Tier3 events were those that were neither Tier 1 nor Tier 2.
Other Analysis : The safety and immunogenicity results for individuals with confirmed
stable HIV disease will be summarized descriptively at a later time .Furthermore, VE may
be assessed if there is a sufficient number of COVID -19 cases in this group of participants.
The safety and immunogenicity results for individuals 16 to 55 y ears of age vaccinated with
study intervention produced b y manufacturing “Process 1 ” or “Process 2” will be
summarized descriptively.
All severe COVID -19 cases occurring after Dose 1 were summarized descriptively .
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Page 21RESULTS –PHASE 1
ParticipantDisposition and Demography: BNT162b1: In the younger age group, all
participants randomized to the 10-µg, 20-µg, and 30-µg dose groups received both doses of
BNT162b1 or placebo. All participants randomized to the 100 -µg dose group received
Dose1 of BNT162b1 or placebo. The IRC determined not to administer the second dose of
100µg due to rea ctogenicity . At the time of the data cutoff date (24 August 2020) , 11of 12
participants in this group received Dose 2 of BNT162b1 at 10 µg but results for Dose2 are
not yet available at the time of this report. After the data cutoff date (24 August 2020), the
remaining participant received Dose 2 of BNT162b1 at 10 µg. All participants in the older
age group randomized to each dose group received both doses of BNT162b1 or placebo .
Overall, for the safety population, most participants were White (37 [82.2%]; 14 [93.3%] for
the 100-µg dose group) in both the y ounger age group and older age group. Median age was
35.0 years in the y ounger age group (35.0 years for the 100- µg dose group) and 69.0 y ears in
the older ag e group. There was a higher representation of males in the y ounger age group
(up to 30 µg) (28[62.2%]). There was a higher representation of females in y ounger 100- µg
dose group (9 [60.0%]) and in the older age group (32 [71.1%]).
BNT162b2: All participants randomized to each dose group in the y ounger and older age
groups received both doses of BNT162b2 or placebo.
Overall, most participants were White in the y ounger age group (39 [86.7%]), and all
participants were White in the older age group (45 [1 00%]). Median age was 37.0 y ears in
the younger age group and 68.0 y ears in the older age group. There was a higher
representation of females in both the y ounger (26 [57.8%]) and older (28 [62.2%]) age
groups.
Immunogenicity Results: In general, a modest neutralizing immune response was observed
in both the y ounger and older age groups after the first dose. A much more robust immune
response was observed 7 days after the second dose of either BNT162b1 or BNT162b2 at all
dose levels in both the y ounger and older age groups. Antibody levels at the last time point
tested were still substantially above those at baseline.
In the younger age group:
At 7 days after Dose 2, SARS -CoV-2 50% neutralizing GMTs in the 20-µg and 30 -µg
dose groups were higher for BNT162b2 recipients than for BNT162b1 recipients. The
GMTs were similar in the 10- µg dose group for both recipients. At 1 month after Dose 2
(Day52), GMTs remained substantially higher than those at the earlier time points after
Dose1 for both BNT162b1 and BNT162b2 recipients.
From before vaccination to 7 day s after Dose 2, GMFRs of SARS -CoV-2
50%neutralizing titers were substantiall y high for BNT162b1 and BNT162b2 recipients
at the 30- µg dose level.
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Page 22From before vaccination to 7 day s after Dose 2, all participants at the 30- µg dose level
who received BNT162b1 or BNT162b2 achieved a ≥4-fold rise in SARS CoV -2
50%neutralizing titers.
In the older age group:
At 7 days after Dose 2, SARS -CoV-2 50% neutralizing GMT in the 30- µg dose group
was higher for BNT162b2 recipients than for BNT162b1 recipients. At 1 month after
Dose2 (Day52), the SARS -CoV-2 50% neutralizing GMTs in the 30 -µg dose group
were similar for both BNT162b1 and BNT162b2 recipients.
From before vaccination to 7 day s after Dose 2, the GMFR of SARS -CoV-2
50%neutralizing titers were substantiall y high for BNT162b1 and BNT162b2 recipients
at the 30- µg dose level.
From before vaccination to 7 day s after Dose 2, most participants who received
BNT162b 1or BNT162b 2at the 30- µgdose level achieved a ≥4-fold rise in SARS -CoV-2
50%neutralizing titers.
Immunogenicity Conclusions:
Both BNT162b1 and BNT162b2 elicited robust SARS- CoV-2 neutraliz ing antibody
response7 days after Dose 2 in younger and older adults, based on GMTs, GMFRs,
proportions of participants achieving a ≥4-fold rise in neutralizing titers, and reverse
cumulative distribution curves (RCDCs). Neutraliz ing antibody response was maintained
through Day 52 and was similar for the candidates within the corresponding age and dose
groups.
Both BNT162b1 and BNT162b2 elicited substantial rises in antigen binding IgG levels
7days after Dose 2, based on GMCs, GMFRs, and proportions of participants achievi ng
a ≥4-fold rise in IgG -antigen specific binding. Responses were maintained through
Day52.
In the 100- µg dose group, SARS -CoV-2 neutraliz ing antibody response modestly
increased b y 3weeks after Dose 1 of BNT162b1, but neutralizing antibody response
returned to levels similar to baseline by 7weeks after Dose 1.
These data support the need for a 2 -dose vaccination series.
Safety Results: Overall, reactogenicity events were well tolerated and short -lived(median
durations 1.0 to 4.0 days). All partici pants returned to receive their second dose. All AEs as
a result of reactogenicity events resolved without sequelae.
For local reactions in both age groups, pain at the injection site (58.3% to 100.0%),
redness(0% to 16.7%), and swelling (0% to 25.0%) were reported for BNT162b1
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Page 23recipients, which were more frequent than for BNT162b2 recipients: pain at the injection
site (33.3% to 91.7%), redness (0% to 8.3%), and swelling (0% to 16.7%). I n general,
frequencies of local reactions were observed to be hig her with increased dose level.
The frequency of local reactions was lower in the older age group compared to the
younger age group. The frequency of pain at the injection site, the most frequently
reported local reaction, was lower in the older age groups after 30µg BNT162b1
(91.7%and 75.0%) and after 30 µg of BNT162b2 (75.0% and 66.7% for Dose 1 and
Dose2, respectivel y), compared to the younger age groups after 30 µg of BNT162b1
(100.0% for both Dose 1 and Dose 2) and 30 µg of BNT162b2 (91.7% and 83.3% for
Dose1 and Dose 2, respectively ).
BNT162b2 recipients in the older age group reported lower frequencies of local reactions
compared with BNT162b1 recipients in the older age group. In the older 30 -µg
BNT162b2 group, pain at the injection site was lower after Dose 1 (75.0%) and
Dose2(66.7%) than in the older 30 -µg BNT162b1 group after Dose 1 (91.7%) and
Dose2 (75.0%).
Common sy stemic events in both age groups after either Dose 1 or Dose 2 included
fatigue (16.7% to 83.3%), headache (25.0% to 100%) , chills (8.3% to 66.7%), fever (0%
to 75.0%), and muscle pain (8.3% to 75.0%) for BNT162b1 recipients up to 30 µg, which
were more frequent than BNT162b2 recipients up to 30 µg: fatigue (8.3% to 75.0%),
headache (0% to 66.7%), chills (0% to 58.3%), fever (0% to 16.7%), and muscle pain
(0% to 58.3%). In general, frequencies of s ystemic events were observed to be higher
with increased dose level.
The frequency of systemic events was lower in the older age group compared to the
younger age group. The freque ncy of fatigue was lower in the older age groups after
30 µg of BNT162b1 (50.0% and 66.7%) and after 30 µg of BNT162b2 (25.0% and
41.7% for Dose 1 and Dose 2, respectively ), compared to the y ounger age groups after
30µg of BNT162b1 (50.0% and 83.3%) and a fter 30µg of BNT162b2 (41.7% and
75.0%) for Dose 1 and Dose 2, respectively .
BNT162b2 recipients in the older age group reported lower frequencies of systemic
events compared with BNT162b1 recipients in the older age group. The frequency of
fatigue was lower in the older 30 -µg BNT162b2 group (25.0% and 41.7% for Dose 1 and
Dose2, respectivel y) than in the older 30 -µg BNT162b1 group (50.0% and 66.7% for
Dose1 and Dose 2, respectively ).
Most AEs were mild or moderate in severity . Most related AE swere similar to the solicited
reactogenicity events reported in the e -diary. Few severe AE were reported but were
considered not related to study intervention.
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Page 24There were no SAEs reported in the BNT162b1 groups (across all dose levels). There was
1SAE reported in the BNT162b2 30 -µg younger age group (neuritis).
Transient decrease in lymphocy tes were observed in all age and dose groups 1 to 3 day s after
Dose1, which resolved by 6 to 8 day s after Dose 1.
There were no clinicall y important findings from phy sical examinations.
BNT162b2 demonstrated a favorable reactogenicity and safet y profile compared with
BNT162b1, contributing to the selection of BNT162b2 for Phase 2/3 development.
Safety Conclusions:
All doses tested for BNT162b1 and BNT162b2 (10 µg, 20 µg, and 30 µg) were safe and
well tolerated except for BNT162b1 at 100 µg, which was discontinued after the first
dose due to the reactogenicity profile.
Reactogenicit y was generally higher after Dose 2 than Dose 1.
The frequency of local and sy stemic reactogenicity was generall y lower for BNT162b2
compared to BNT162b1 especiall y after the second dose.
Reactogenicit y events after each dose for both BNT162b1 and BNT162b2 in older adults
were milder an d less frequent than those observed in y ounger adults. The majority of
reactogenicity events were mild or moderate in severity .
Most AEs were mild or moderate. There were discontinuations because of AEs. There
was 1 SAE (neuritis; unrelated to vaccination) reported in a younger participant in the
BNT162b2 30 µg group.
Overall, fewer AEs were experienced b y participants who received BNT162b2 compared
with those who received BNT162b1, with the least number of participants experiencing
AEs in the BNT162b2 older age group. Few severe AEs in the older age group after
BNT162b2 were observed, and all were considered unrelated to stud y intervention.
Clinical laboratory evaluations showed a transient decrease in l ymphocytes that was
observed in all age and dose groups after Dose 1, which resolved within a few day s, were
not associated with any other clinical sequelae, and were not considered clinically
relevant.
BNT162b2 at 30 µg was selected to proceed into the Phase 2/3 portion of the study
because this dose and construct provided the optimum combination of a favorable
reactogenicity profile and a robust immune response.
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Page 25RESULTS –PHASE 2
ParticipantDisposition and Demography: The first 360 participants enrolled as part of
Phase2 were randomized 1:1 (180participants each) to the BNT162b2 and placebo groups.
Among participants randomized to the BNT162b2 group, 88 participants were in the younger
age group (18 to 55 years of age) and 92 participants were in the older age group (56 to
85years of age).
Exceptfor 1 participant in the BNT162b2 younger age group who was withdrawn after
Dose1 but before Dose 2 and 1 participant in the placebo group ( who had not y et received
Dose2 at the time of data cutoff date [02 September 2020 ]), all other participants recei ved
both doses of study intervention. One participant noted above in the BNT162b2 y ounger age
group was withdrawn from the study (after Dose 1 but before Dose 2) because of an SAE of
gastric adenocarcinoma 23 day s after receiving Dose 1.
From 7 day s afterDose2 to the data cutoff date of 14 November 2020, 1 additional
participant in the BNT162b2 older age group was withdrawn from the study because of an
SAE of cardiac arrest 60 day s after receiving Dose 2, which resulted in death. The death was
assessed by the investigator as not related to the study intervention.
Demographic characteristics for Phase 2 were similar in the BNT162b2 group and the
placebo group for the safety population. The male/female split was approximately 50/50 for
both vaccine groups and also for both age groups within the BNT162b2 group.
Overall, most participants were White (85.8%), followed by Black or African
American (9.2%). The proportions of Hispanic/Latino participants were similar in the
BNT162b2 and placebo groups (8.9% an d 11.1%, respectivel y). Within the BNT162b2
group, the younger age group had 14.8% of Hispanic/Latino participants and the older age
group had 3.3%.
The median age was 56.0 y ears overall. Median age was 44.0 y ears for the BNT162b2
younger age group and 6 5.0 years for the BNT162b2 older age group.
Demographic characteristics for the 336 participants included in the Dose 2 evaluable
immunogenicity population were similar to those in the safet y population in Phase 2.
Demographic characteristics for the Dose 2 all-available immunogenicit y population were
similar to those in the Dose 2 evaluable immunogenicity population.
Immunogenicity Results:
Immunogenicit y results from 360 participants in Phase 2 of this study demonstrated that
BNT162b2 at 30 µg elicited ro bust SARS -CoV-2 neutralization and S1 -binding IgG
antibody responses at 1 month after Dose 2 similar to those previousl y observed in
Phase1 of the stud y. Notably, SARS -CoV-2 neutralizing titers were higher in the
younger age cohort compared with the older age cohort .
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Page 26S1-binding GMCs were generall y higher in the younger age cohort compared to the older
age cohort, again concordant with observations in the Phase 1 portion of the study .
Safety Results:
Across age groups, local reactions were generally similar in frequency after each dose,
and systemic events generally increased in frequency and severity after Dose 2 compared
to Dose 1. L ocal and s ystemic reactogenicit yevents were well -tolerated and short -lived.
Reactogenicit yevents after each dose of B NT162b2 in older adults were generall y milder
and less frequent than those observed in younger adults. The majority of reactogenicity
events were mild or moderate in severit y. No Grade 4 events were reported.
AEs in participants were low in frequency , andmost AEs were mild or moderate in
severity. There were no SAEs or discontinuations because of AEs that were assessed as
related by the investigator. There was 1 death in the BNT162b2 group (cardiac arrest)
that was assessed as not related to study intervention.
The reactogenicit y and AE profile after BNT162b2 30 µg evaluated in 360 participants
was consistent with the safety profile observed after BNT162b2 30 µg in Phase 1.
BNT162b2 at 30 µg was safe and well tolerated up to 7 day s after Dose 2 and up to at
least 2 months of follow-up .
RESULTS –PHASE 2/3
ParticipantDisposition and Demography: The disposition of the first 37,796 participants
(including the 360 participants in Phase 2) randomized was similar in the BNT162b2 and
placebo groups. Most participants randomized ( ≥98.1%) received Dose 1 and Dose 2. There
were 121 (0.6%) participants in the BNT162b2 group and 111 (0.6%) participants in the
placebo group discontinued from the vaccination period who are continuing in the study to be
followed for safet y. The most frequently reported reasons for discontinuation from the
vaccination period included: no longer meets eligibility criteria, withdrawal by subject, and
AE. Few participants in the BNT162b2 and placebo groups were withdrawn from t he study
(1.0% and 1.4%, respectively ), and most were withdrawals b y the participant, or they were
lost to follow -up. Eight participants in the BNT162b2 group and 5 participants in the
placebo group were withdrawn due to an AE.
One participant was rando mized but did not sign an I CD and is not included in any analysis
population. HIV -positive participants (120 participants) are included in this summary but
were not included in the anal yses of the overall study objectives. Because of a dosing error,
2 participants received an additional dose of BNT162b2 (30 µg) at an unscheduled visit after
receiving 1 dose of BNT162b2 (30 µg) and 1 dose of placebo.
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Page 27Due to a data -related issue for this ongoing stud y that is being corrected, 2 participants were
reported as ‘discontinued from the vaccination period but continue in the study ’ with the
reason as lost to follow -up, although the participants discontinued from the study .
The total of 37,796 participants excluded 4 participants (5 participant identification numbers)
with special data issues: 2 participant identification numbers from 1 multi-enrolled
participant and 3 participants whose actual treatment was not confirmed in IRT at the time of
data cutoff.
From Dose 1 to the data cutoff date (14 November 2020), disposition of all
43,548participants randomized (which excludes 3 participants whose actual treatment was
not confirmed in IRT at the time of the data cutoff and 2additional participant identification
numbers from 1- multi-enrolled participant ) was generall y similar in the BNT162b2 and
placebo groups. Almost all participants randomized received Dose 1 (99.8%) and
approximately 94.2%of participants received Dose 2 at the cutoff date for the anal yses in
this CSR. At the ti me of the data cutoff, 137 (0.6%) participants in the BNT162b2 group and
129(0.6%) participants in the placebo group were discontinued from the vaccination period
but were continuing in the study for safety follow-up. The most frequentl y reported reasons
for discontinuation from the vaccination period included: no longer meets eligibility criteria,
withdrawal b y participant, and AE.
Of the 181 (0.8%) and 263 (1.2%) participants who were withdrawn from the study in the
BNT162b2 and placebo groups, respectively , most were withdrawn after Dose 1 and before
Dose2 (133 [0.6%] in the BNT162b2 group and 168 [0.8%] in the placebo group). Most of
these were withdrawals by the participant, or they were lost to follow -up. Eight participants
in the BNT162b2 group a nd 6 participants in the placebo group were withdrawn because of
an AE. Nine participants withdrew from the stud y due to pregnancies. There were 6 deaths:
2 in the BNT162b2 group and 4 in the placebo group. None of the deaths were assessed b y
the investi gator as related to study intervention.
Due to a data -related issue for this ongoing stud y that is being corrected, a total of
3 participants were reported as ‘discontinued from the vaccination period but continue in the
study’ with the reason as lost to follow-up (inclusive of the 2 participants who were part of
the ~38,000 participants), although the participants discontinued from the study .
The Phase 2/3 total of 43,548 randomized participants excluded 4participants (5 participant
identification num bers) with special data issues: 1 multi-enrolled participant (2 participant
identification numbers) and 3participants whose actual treatment was not confirmed in I RT
at the time of data cutoff . All 4participants (5 participant numbers)were part of the ~38,000
population.
Demographic characteristics for the 37,706 Phase 2/3 participants (who had a median
2months of follow -up after Dose 2) were similar in the BNT162b2 and placebo groups.
Overall, most participants were White (82.9%), with 9.3% Black par ticipants and 4.3% Asian
participants, and other racial groups were <3%. There were 28% Hispanic/Latino
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Page 28participants. Median age was 52 years and 50.6% of participants were male. The younger
and older age groups were 57.8% and 42.2% of participants, respe ctively. Obese participants
made up 35.1% of this safety population.
Within each age group, most demographic characteristics were similar in the BNT162b2
group and the placebo group. There was a lower proportion of non -Hispanic/non -Latino
participants in the younger BNT162b2 and placebo groups (65.4% and 65.6%, respectively )
than in the older BNT162b2 and placebo groups (79.8% and 79.4%, respectively ).
Demographic characteristics for all 43,448 Phase 2/3 participants included in the safet y
population to d ate were similar in the BNT162b2 and placebo groups for the safet y
population. Overall, most participants were White (82.2%) and non -Hispanic/non -Latino
(73.3%), median age was 51.0 years, and 49.1% were female. There were 9.7% Black or
African American, 4.3% Asian, 2.4% Multiracial, 0.7% American Indian or Alaskan native,
and 0.2% Native Hawaiian or other Pacific Islander participants included in the safet y
population. Race was not reported for 0.5% of the participants. There were 58.9% of
participants in the younger age group. Obese participants made up 34.7% of this safet y
population .
Within each age group, most demographic characteristics were similar in the BNT162b2
group and the placebo group. There was a lower proportion on non -Hispanic/non -Latino
participants in the younger BNT162b2 and placebo groups (68.1% and 68.3%, respectivel y)
than in the older BNT162b2 and placebo groups (80.9% and 80.6%, respectively ).
Demographics of participants in the final anal ysis evaluable efficacy population for
participants without evidence of infection priorto 7days after Dose 2 were similar in
BNT162b2 and placebo groups. This anal ysis population had generally similar
demographics compared to the safet y population.
Demographic characteristics for the final anal ysis Dose 2 all -available efficacy population
and the evaluable population without evidence of infection prior to 14 day s after Dose 2 were
similar to the Dose 2 evaluable efficacy (7 days) population
Efficacy Results:
Interim Analysis 1
The first primary efficacy objective met success criteria. BNT162b2 achieved vaccine
efficacyof 95.5% with a 95% credible interval of 88.8% to 98.4% among participants
without evidence of infection before and during vaccination regimen , and a >99.99%
posterior probability for the true vaccine efficacy greater than 30% conditioning on
available data.
All 7 severe COVID -19 cases (after Dose 1) were observed in the placebo group, as of
the interim anal ysis cutoff dates.
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Page 29Final Analysis
Evaluable Efficacy Population
In the final efficacy analysis, among participants without evidence of SARS -CoV-2 infection
before and during vaccination regimen, VE against confirmed COVID -19 occurring at least
7days after Dose 2 was 95.0%, with 8 COVID -19 cases in the BNT162b2 group compared
to 162 COVI D-19 cases in the placebo group. The 95% credible interval for the vaccine
efficacy was 90.3% to 97.6%.
For the second primary endpoint, VE against confirmed COVID -19 occurring at least 7 days
after Dose 2 in participants with or withou t evidence of SARS -CoV-2 infection before and
during vaccination regimen was 94.6%, with 9 and 169 cases in the BNT162b2 and placebo
groups respectively . The posterior probability of >99.99% for the true VE greater than 30%
met the prespecified success criterion of >98.6% for this endpoint. The 95% credible interval
for the vaccine efficacy was 89.9% to 97.3%.
Observed VE was very high for the first primary efficacy endpoint across subgroups of age,
sex, race/ethnicity , and country , as VE was >93% in all subgroups, with the exception of “all
others” race group (89.3% VE) and Brazil (87.7% VE).
For the secondary efficacy endpoint , observed VE against confirmed COVID -19 occurring at
least 14 day s after Dose 2 in participants without evidence of SARS- CoV-2 infection before
and during vaccination regimen, was 94.2%, with 8 and 139 cases in the BNT162b2 and
placebo groups, respectively . The posterior probability of >99.99% for the true VE greater
than 30% met the prespecified success criterion of >98.6% for this endpoint. The 95%
credible interval for the vaccine efficacy was 88.7% to 97.2%.
Similarly, among participants with or without evidence of SARS -CoV-2 infection before and
during vaccination regimen, VE against confirmed COVID -19 occurring at least 14 day s
after Dose 2 was 94.4%, with 8 and 144 cases in the BNT162b2 and placebo groups
respectivel y. The posterior probability of >99.99% for the true VE greater than 30% met the
prespecified success criterion of >98.6% for this endpoint. The 95% credible inter val for the
vaccine efficacy was 89.1% to 97.3%.
Among participants without evidence of SARS -CoV-2 infection before and during
vaccination regimen, observed VE of 66.3% against severe COVID -19 occurring at least
7days after Dose 2 did not me et theprespecified success criterion of theposterior probability
>98.6%, due to the small number of severe cases (1 in the BNT162b2 group, 3 in the placebo
group) observed withinthe prespecified timeframe of ≥7 days after Dose 2 in the study .
The efficacy analyses using CDC defined sy mptoms to identify a COVID -19 case gave
similar efficacy results as the primary endpoint.
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Page 30All-Available Efficacy Population
The early onset of protection is readily apparent from cumulative incidence curves, which
show that dise ase onset tracks conjointly for BNT162b2 and placebo until approximately
14days after Dose 1, at which point the curves diverge, with cases steadil y accumulating in
the placebo group, while remaining virtually flat after BNT162b2.
Among all participants ( regardless of evidence of infection before or during the vaccination
regimen) 50 cases of COVID -19 occurred after Dose 1 in the BNT162b2 group compared
with 275 cases in the placebo group, indicating an estimated VE of 82% ( 2-sided 95% CI:
75.6%, 86.9%) a gainst confirmed COVID -19 occurring after Dose 1 , with VE of 52.4%
(95%CI: 29.5%, 68.4%) between Dose 1 and Dose 2.
Among the total of 10 severe COVID- 19 cases observed after Dose 1, only 1severe case was
seen in BNT162b2 recipients compared to 9 severe COVID-19 cases in placebo recipients;
these results, as well as case splits between Dose 1 and Dose 2 and after Dose 2, were
consistent with overall efficacy seen against COVID -19.
In conclusion, the final efficacy results show that BNT162b2 at 30 µg provi ded protection
against COVID -19 in participants who had no evidence of prior infection with SARS -CoV-2,
including across demographic subgroups, with severe cases observed predominantly in the
placebo group.
Safety Results:
Across age groups, local reactions were generally similar in frequency after each dose,
and systemic events generally increased in frequency and severity after Dose 2 compared
to Dose 1. Local and systemic reactogenicit yevents were well -tolerated and short -lived
(median durations of 1.0 to 2.0 day s).
Reactogenicit y events after each dose of BNT162b2 in older adults were generall y milder
and less frequent than those observed in younger adults. The majority of reactogenicity
events were mild or moderate in severity. No Grade 4 events were reported other than
fever in 2 participants: 1 participant in the y ounger BNT162b2 group that began on Day 2
after Dose 2 and lasted 1 day, and 1 participant in the older BNT162b2 group that began
on Day4 after Dose 1 and lasted for 1 day.
The reactogenicit y profile after BNT162b2 30 µg evaluated in 8183 participants was
consistent with the reactogenicity profile observed after BNT162b2 30 µg in Phase 1 and
Phase 2.
In the ~38,000 participants in Phase 2/3 with a median follow-up of at least 2 months
after Dose 2, AEs were reported in 27.0% of participants in the BNT162b2 group, and
most AEs were mild or moderate in severity . At the time of the data cutoff date, the
number of participants with AEs in the BNT162b2 group was greater as compared with
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Page 31the placebo group (12.5%), which upon anal ysis, was attributed to reactogenicity events
reported as AEs within 7 day s after each dose.
Analyses of the data for each population at the data cutoff date of 14 November 2020
(~38,000 with a median follow -up of 2 months after Dose 2, ~19,000 with at least
2months of follow -up after Dose 2, and ~44,000 enrolled participants with variable
length of follow -up) did not identify any new safety signals with longer follow -up or by
examining all of the AEs reported in the database.
At the time of the data cutoff date, there were 4 related SAEs in the BNT162b2 group
(lymphadenopathy ; shoulder injury related to vaccine administration [SI RVA],
erroneousl y administered into or near the shoulder joint capsule ;ventricular arrh ythmia;
and lower back pain and bilateral lower extremity pain with radicular paresthesia
[uncoded term] ), and few participants in the BNT162b2 group (0.2%) were withdrawn
because of AE s. There were 2 deaths in the BNT162b2 group (arteriosclerosis and
cardiac arrest) and 4 deaths in the placebo group that were assessed as not related to stud y
intervention.
Overall, BNT162b2 at 30 µg was well tolerated with a maximum follow -up time of up to
14 weeks after Dose 2.
Overall Co nclusion(s):
In Phase 1, BNT162b2 at 30 µg induced a robust immune response in both younger and
older adults, and the reactogenicity profile was also satisfactory in both younger and
older adults. BNT162b2 at 30 µg was selected for further development in the Phase 2/3
part of the stud y.
In Phase 2 , BNT162b2 at 30 µg elicited robust SARS -CoV-2 neutralization and
S1-binding IgG antibod y responses, consistent with results observed in Phase 1.
In Phase 2 /3, BNT162b2 at 30µg provided protection against COVID -19 in participants
irrespective of evidence of prior infection with SARS -CoV-2, including across
demographic subgroups, with severe cases observed predominantl y in the placebo group.
The tolerability and safety profile of BNT162b2 30 µg was acceptable, and no c linically
significant safet y findings other than mild or moderate reactogenicit y and mild and
reversible l ymphadenopathy were identified.
Overall, the risk -benefit of BNT162b2 30 µg remains favorable .
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